Microbial colonization influences early B-lineage development in the gut lamina propria

摘要

The RAG1/RAG2 endonuclease (RAG) initiates the V(D)J recombination reaction that assembles immunoglobulin heavy (IgH) and light (IgL) chain variable region exons from germline gene segments to generate primary antibody repertoires. IgH V(D) J assembly occurs in progenitor (pro-) B cells followed by that of IgL in precursor (pre-) B cells. Expression of IgH and IgL (Ig or Ig) chains generates IgM, which is expressed on immature B cells as the B-cell antigen-binding receptor (BCR). Rag expression can continue in immature B cells, allowing continued Ig V(D)J recombination that replaces the initial VJ exon with one that generates a new specificity. This 'receptor editing' process, which can also lead to Ig V(D)J recombination and expression, provides a mechanism whereby antigen encounter at the Rag-expressing immature B-cell stage helps shape pre-immune BCR repertoires. As the major site of postnatal B-cell development, the bone marrow is the principal location of primary immunoglobulin repertoire diversification in mice. Here we report that early B-cell development also occurs within the mouse intestinal lamina propria (LP), where the associated V(D)J recombination/receptor editing processes modulate primary LP immunoglobulin repertoires. At weanling age in normally housed mice, the LP contains a population of Rag-expressing B-lineage cells that harbour intermediates indicative of ongoing V(D)J recombination and which contain cells with pro-B, pre-B and editing phenotypes. Consistent with LP-specific receptor editing, Rag-expressing LP B-lineage cells have similar V_H repertoires, but significantly different V repertoires, compared to those of Rag2-expressing bone marrow counterparts. Moreover, colonization of germ-free mice leads to an increased ratio of Ig-expressing versus Ig-expressing B cells specifically in the LP. We conclude that B-cell development occurs in the intestinal mucosa, where it is regulated by extracellular signals from commensal microbes that influence gut immunoglobulin repertoires.%原发性B-细胞的生成被认为仅限于骨髓，但 Frederick Alt及同事在这篇文章中发表了令人 吃惊的发现：它也发生在肠道中，在那里它受 到肠道微生物的刺激。作者描述了出生后小鼠 的正在小肠粘膜内（具体是在粘膜的固有层中） 发育的一组早期B-细胞。B-细胞的生成在断奶 时达到高峰，当微生物在无菌小鼠体内定植时 增加。这些B-细胞与从骨髓生成的B-细胞是不 同的，其群体可能是由共生微生物决定的。